Papillary Renal Cell Carcinoma: Demographics, Survival Analysis, Racial Disparities, and Genomic Landscape

Papillary renal cell carcinoma (PRCC) is the second most common histological subtype of renal cell cancer. This research aims to present a large database study highlighting the demographic, clinical, and pathological factors, racial disparities, prognosis, and survival of PRCC. The clinical and demographic data were extracted from the Surveillance, Epidemiology, and End Results (SEER) database, and molecular data was cured from the Catalogue Of Somatic Mutations in Cancer (COSMIC) database. PRCC had a median age of diagnosis at 64 years, with a higher incidence in men (77%), and Whites (68%). 70.3% of cases were Grades I–IV (13, 53, 31, and 3%, respectively). In patients with known data, 85% were localized to the kidney, and 84% of cases were 7 cm in size. No metastasis occurred in 97% of the known data. The most common treatment offered was surgical resection (9%). The 5-year overall survival was 79%, with patients undergoing surgery having a 90.6% 5-year survival. Multivariable analysis revealed age > 60 years, Black race, poor histologic differentiation, distant metastases, and tumor size > 10 cm as independent risk factors for mortality. The most common mutations identified from the COSMIC database were MET, KMT2D, KMT2C, ARID1A, and SPEN. PRCC affects male individuals in the sixth decade of life. Increased age, Black race, distant metastases, and tumors > 10 cm are associated with a worse prognosis. Surgical resection offers a favorable survival outcome. Next-generation sequencing (NGS) could identify potentially targetable alterations and future personalized therapeutic approaches.

This study aims to provide one of the largest and most up-to-date database studies aimed at investigating the demographic, clinical, and pathological factors affecting the prognosis and survival of patients with PRCC.

Introduction
Renal cell carcinomas (RCC) are subdivided into clear cell RCC and non-clear cell RCC.Non-clear cell RCC comprises papillary RCC (PRCC), chromophobe RCC, oncocytic RCC, and collecting duct carcinoma (1).Histologically, PRCC is differentiated from clear cell RCC by the existence of basophils or eosinophils in the papillary or tubular structures of the kidney (2).Papillary RCC is the second most common RCC, accounting for 10-15% of all RCC cases.The peak incidence is in the sixth to eighth decades of life, with males being approximately twice as likely as females to develop PRCC.
Asian American and Pacific Islander patients have the lowest incidence of renal cancer in the United States when compared to patients of other ethnicities.African Americans and White American patients had a similar 5-year survival rate (approximately 75%).Risk factors included patients with end-stage renal disease on hemodialysis, hypertension, obesity, smoking, male sex, and family history (2)(3)(4).Traditionally, PRCC has been classified as Types 1 and 2. Type 1 PRCC is associated with chromosomes 7 and 17 gains, while Type 2 PRCC is more heterogenous with gains in chromosomes 12, 16, and 20 (4).The divisions were based on morphology as Type 1 PRCC has slender papillae lined by a single layer of small basophilic cells and Type 2 PRCC has broader papillae, multiple layers of eosinophilic cells, nuclear pseudo stratification, and larger nucleoli (4,5).In 2022, the World Health Organization (WHO) classification of PRCC adapted to focus on phenotypes and molecular traits as Types 1 and 2 mixtures were common (5).The recent reclassification of PRCC integrating morphology, immunophenotype, and molecular analysis delineates newer subtypes such as biphasic squamous alveolar RCC (bearing MET mutations), biphasic hyalinizing psammomatous RCC (bearing NF2 mutations), papillary renal neoplasm with reverse polarity (bearing chromosomes 7 and 17 gains, GATA3 and L1CAM nuclear positivity, and KRAS mutations), Warthin-like PRCC, and thyroid-like follicular RCC (5)(6)(7)(8).
Clinical features of PRCC include weight loss, flank pain, palpable renal mass, hematuria, fatigue, fever, and night sweats although many patients are usually asymptomatic in the early stages (9).While renal masses can be identified on ultrasound, the first-line modalities for diagnostics are abdominal CT or MRI (with IV contrast) usually revealing homogeneous solid masses (10)(11).At the time of diagnosis, PRCC tumors are more likely to be localized.If metastases occur, it favors the lung, bone, liver, and brain, and have a high preference for lymph node involvement.Localized PRCC confined to a kidney is managed with partial or radical nephrectomy, ablation, or active surveillance.There is a 5-year recurrence-free survival (RFS) of 95.8% and a 10-year RFS of 73% with patients undergoing partial combination therapies (surgery and adjuvant chemoradiation) at 1 year was 62.4% (95% CI, 48.0-73.9),and at 5 years was 11.4% (95% CI, 4.3-22.2).The best overall longterm survival was observed with surgery followed by surgery and adjuvant radiation, whereas the combination therapies (surgery and adjuvant chemoradiation) showed no significant improvement in survival (P < 0.0001) (Figure 2B).In regional and distant-stage diseases, there were no significant differences in survival in those that were diagnosed between 2000 and 2010, and 2011 and 2018 (P = 0.1115) (Figure 3).The cases of PRCC is consistently spiking since 2000 (Figure 4).The increase in the number of cases may be related to the improvement of diagnostic modalities over the period of 18 years.
For survival analysis, those cases are included which are microscopically confirmed, malignant behavior, and patients with known age.The cases excluded from the survival analysis software were, all death certificates only and autopsy only, alive with no survival time.

Results
In total, 23803 cases of PRCC were identified from 2000 to 2018 in the SEER database.A total of 431 samples were analyzed from PRCC for mutations in the COSMIC database.

Demographic data and tumor characteristics
The median age was found to be 64 years with a standard deviation (SD) of 11.8 years.Most were aged < 70 years, that was around 16,670 (70%) cases.76.7% of the cases were males.The majority of the cases were Whites (68.5%) by race.The grade of 70.3% of the cases were known, of which 52.7% were of Grade II.84.6% of the cases were localized (to the kidneys).The tumor size was ≤7 cm in 83.6% of the cases when known (Table 1).

Treatment characteristics and distant metastasis at the time of diagnosis
Of the total cases, the chemotherapy statuses were unknown in 91.4% of the cases, but they underwent surgery without radiation.Only 1.4% of the cases had chemotherapy (any systemic therapy) (Figure 1A).
The site of metastases at presentation was unknown in 37% of the cases and was known in 63.0% of the cases.There were no metastases in majority (96.7%) of the known cases.The most common site of metastasis was the lungs (1.3%) (Figure 1 B).
COSMIC database revealed alterations in MET in 63 of 709 (9%) PRCCs tested for missense mutations.There were 14 copy number gains identified from the 286 (4.8%) tested.MET missense mutations were seen in one out of seven copy number gains.

Discussion
This study includes one of the largest groups of patients with PRCC.The Median age of diagnosis was 64 11.8 years, and a higher incidence in men (76.7%) was noted.The majority of cases were localized (84.6%) with no metastases in 96.7% of the known cases.
The cases of PRCC is consistently increasing since 2000 to 2018, likely reflecting better diagnostics and improved screening guidelines.Per previous reports, PRCC is prevalent in the sixth to eighth decades of life and has a male sex preference with a male-to-female ratio of 1.5-2:1 (2, 12).Mendhiratta et al. (2) reported that there are roughly three times as many Black patients diagnosed with PRCC with relative to other races.Our analysis showed a frequency of PRCC in 27.5% of Black patients and a frequency of 68.5% in White patients.It is important to note that our study included a larger number of White participants (16,311) compared to Black participants (6557).In patients where tumor metastasis was known, 96.7% reported no metastasis.If metastasis occurred, common locations included the bone, brain, liver, and lungs.These findings are consistent with what has been reported in the literature (2).The overall observed 5-year survival rate was recorded as 78.6%, and previous studies reported a value of 61% (13).
The goals of therapy are dependent on the extent of the disease.Treatment options for localized PRCC include surgical removal (partial or radical nephrectomy), ablation (cryoablation, radiofrequency ablation, or microwave ablation), or active surveillance, similar to the treatment options for localized clear cell RCC (2,12).Small PRCC (4 cm) confined to the kidney can be managed with nephron-sparing surgery (partial nephrectomy), as it produces satisfactory patient outcomes (12,14).Radical nephrectomy may be performed depending on the extent of disease, tumor location, presence of metastases, as well as additional patient-specific factors including patient comorbidities and overall health status.Surgical resection is typically the definitive therapy for localized disease without metastases as it offers the greatest chance of cure (12,14,15).
Treating advanced PRCC takes into consideration histopathology, molecular variations, and clinical presentations as these characteristics play a role in therapy response.Most of what is known about treating advanced PRCC comes from our understanding of clear cell RCC (16).Systemic therapy is typically administered as a single therapy or in combination with other agents.Available therapies include programmed cell death protein 1 (PD-1) checkpoint inhibitors (nivolumab and pembrolizumab), programmed cell death ligand 1 (PD-L1) Product-limit survival estimates with number of subjects at risk and 95% confidence limits Product-limit survival estimates with number of subjects at risk and 95% confidence limits Product-limit survival estimates with number of subjects at risk and 95% confidence limits Product-limit survival estimates with number of subjects at risk and 95% confidence limits Product-limit survival estimates with number of subjects at risk and 95% confidence limits Product-limit survival estimates with number of subjects at risk and 95% confidence limits  Although recent WHO reclassifications have a single PRCC category, existing literature classifies PRCC into Types 1 and 2, primarily based on histopathology (12,16,24).Type 1 PRCC is characterized by basophilic cells, small nuclei, and a single layer of cuboidal or columnar epithelial cells (2).It is typically confined to the kidney and is associated with a good prognosis.Type 1 PRCC is associated with hereditary renal cancer syndrome (germline MET) and gains in chromosomes 7 and 17 along with gains in chromosomes 2, 3, 12, 16, and 20 that occur less often (12,18,20,25).Therapeutic agents such as crizotinib, savolitinib, and cabozantinib show promising inhibitor properties against MET, which are useful in treating type 1 PRCC (20).Type 2 PRCC is characterized by eosinophils, psuedostratification, and prominent nucleoli with an unfavorable prognosis as it has an aggressive disease course (2,20).These tumors are less likely to have MET mutations, present at an advanced stage, and run an aggressive course.It may be associated with hereditary leiomyomatosis and renal cell carcinoma (HLRCC) syndrome; germline fumarate hydratase (FH)) (18,20).A focal loss of 9p21 led to a loss of CDKN2A has also been identified in patients with Type 2 PRCC.Poor overall survival is the consequence of patients with mutations in CDKN2A (26).Erlotinib + bevacizumab is the treatment choice for HLRCC (27,28).
PRCC also displays mutations in previously studied cancer-related pathways; these include NF2 (Hippo pathway), SMARCB1 and PBRM1 (SWI/SNF complex), and chromatin modifier pathways (SETD2, KDM6A, and BAP1).Genes in these pathways had high mutation rates in Type 1 and Type 2 PRCC in previous reports.Mutations involving SWI/SNF complex accounted for 20% of mutations in Type 1 and 27% of mutations in Type 2. Chromatin modifier pathways showed alterations in 35% of Type 1 and 38% of Type 2 PRCC.The Hippo pathway revealed mutations in 3% of Type 1 and 10% of Type 2 (25).Tumor clusters have also been identified as part of the pathogenesis of PRCC.Cluster C1 is similar to Type 1 PRCC as it exhibits MET mutations and chromosome 7 gains.Cluster C1 is associated with a better prognosis.Clusters C2a and C2b are similar to Type 2 PRCC.Cluster C2c has a CpG island methylator phenotype (CIMP), which was revealed to have the lowest survival probability (25).
Response to the available therapies is limited in both advanced Type 1 and Type 2 PRCC.Although the treatment approaches are extrapolated from that of clear cell RCC, the response and outcomes do not have the same robust level of evidence (16).In all, treatments have yet to be standardized for advanced diseases.Treatment rather focuses on molecular characterization to provide individualized treatment options to patients (12).Although previous studies have suggested that PRCC has a better prognosis than clear cell RCC, recent studies show this may not be the case as the long-term prognoses were comparable (29).In localized PRCC, surgical  database, and we include data from the COSMIC database on prevalent mutations.Distant metastasis, tumor size >10 cm, Black race, age >60 years, and undifferentiated Grade IV cancers were associated with poor survival rates.Molecular characterization of tumors will better assist in providing patients with a personalized treatment regimen.
resection is favorable to patient outcomes with a reduced metastatic ability compared to clear cell RCC.Advanced PRCC with metastases has a poor prognosis as it has a poor response to therapy due to less effective treatments and the development of resistance (30).While earlier studies showed Type 2 as more aggressive and with more unfavorable outcomes than Type 1, more recent studies have shown that the subtype is not an effective predictive measure of patient survival (31,26).Activations in MET can occur through an activating MET splice site alteration resulting in the skipping of exon 14 or in amplification or copy number gain (CNG) of the chromosomal region harboring MET, at the 7q31 locus of chromosome 7 (32)(33)(34).MET analysis was extensively reviewed, showing 43 cases of MET-altered PRCC with reported CNG, 15 were whole chromosome gain of 7.These were likely to be less responsive to targeted MET inhibition, although rare cases have been reported (35).MET alterations generally impacting the tyrosine kinase domain (amino acid range 1149-1248) have been associated with constitutive activation and are commonly linked to PRCC Type 1 histology, characterized typically as non-aggressive (36).With advancements in clinical trial data concerning immune checkpoints, the standard systemic therapy for PRCC has shifted.Agents targeting the MET proto-oncogene in PRCC have produced promising results; however, these advancements need to be further studied to discern if these targeted therapies have meaningful impact (37).Our study did not find any significant survival difference in those that were diagnosed before 2010 compared to those that were diagnosed after 2010 despite the improvement in therapies, warranting further research and better treatment options for advanced disease.

Limitations
Using a sizable national database, our study aims to describe the clinical and demographic characteristics of patients with PRCC.Our study has similar limitations that are common to many database studies.First, the SEER database does not provide important information for factors such as comorbidities, and associated renal pathologies that could influence the interpretation of results.Second, the SEER database did not include information on the treatment plan and stage-specific management.Additionally, the SEER database does not contain information on the type of chemotherapy, radiation dosing, and scheme or side effects of the various modalities.Lastly, due to the recency of the targeted therapies, SEER database does not give insight into their impact as a treatment option for metastatic disease.

Conclusion
Papillary RCC is the second most common subtype of RCC.This study is one of the largest to date from the SEER
survival estimates with number of subjects at risk and 95% confidence limits +censored logrank

Figure 3 :
Figure 3: Regional and distant stage papillary renal cell carcinoma survival difference among those diagnosed between 2000 and 2010, and 2011 and 2018.

Figure 5 :
Figure 5: Papillary renal cell carcinoma, (A) overall by Age (for the age cutoff was <60 years and >60 years), (B) survival by gender, (C) survival by race, (D) survival by tumor grade, (E) survival by tumor size, (F) survival with tumor stage.

Table 1 :
Demographic profiles and tumor characteristics of papillary renal cell carcinoma.

Table 2 :
Racial disparity table of 23803 patients with papillary renal cell carcinoma.

Table 3 :
Multivariate analysis of independent factors influencing mortality papillary renal cell carcinoma.